Rifaximin is a broad-spectrum antibiotic belonging to the family of Rifamycins and shows its antibacterial activity, in the gastrointestinal tract against localized bacteria that cause infectious diarrhoea, irritable bowel syndrome, small intestinal bacterial overgrowth, Crohn's disease, and/or pancreatic insufficiency.
Rifaximin is sold under the brand name Xifaxan® in US for the treatment of Travellers' diarrhoea and Hepatic Encephalopathy. The chemical name of Rifaximin is (2S,16Z,18E,20S,21S,22R,23R,24R,25S,26S,27S,28E)-5,6,21,23,25-pentahydroxy-27-methoxy-2,4,11,16,20,22,24,26-octamethyl-2,7(epoxypentadeca-[1,11,13]trienimino) benzofuro[4,5-e]pyrido[1,2-a]-benzimidazole-1,15(2H)-dione,25-acetate and the molecular formula is C43H51N3O11 with a molecular weight of 785.9. The structural formula of Rifaximin is:

Rifaximin was first described and claimed in Italian patent IT 1154655 and U.S. Pat. No. 4,341,785. These patents disclose a process for the preparation of Rifaximin and a method for the crystallisation thereof. The process for the preparation of Rifaximin is as depicted in scheme I given below:

U.S. Pat. No. 4,179,438 discloses a process for the preparation of 3-bromorifamycin S which comprises reaction of rifamycin S with at least two equivalents of bromine, per one mole of rifamycin S in the presence of at least one mole of pyridine per each equivalent of bromine and in the presence of ethanol, methanol or mixtures thereof with water at a temperature not above the room temperature. The process is shown in the scheme given below:

U.S. Pat. No. 4,557,866 discloses a process for one step synthesis of Rifaximin from Rifamycin O, which is shown in scheme II given below:

U.S. '866 patent also discloses purification of Rifaximin by performing crystallization of crude Rifaximin from a 7:3 mixture of ethyl alcohol/water followed by drying both under atmospheric pressure and under vacuum. The crystalline form which is obtained has not been characterized.
U.S. Pat. No. 7,045,620 describes three polymorphic forms α, β and γ of Rifaximin. Form α and β show pure crystalline characteristics while the γ form is poorly crystalline. These polymorphic forms are differentiated on the basis of water content and PXRD. This patent also discloses processes for preparation of these polymorphs which involve use of specific reaction conditions during crystallization like dissolving Rifaximin in ethyl alcohol at 45-65° C., precipitation by adding water to form a suspension, filtering suspension and washing the resulted solid with demineralized water, followed by drying at room temperature under vacuum for a period of time between 2 and 72 hours. Crystalline forms α and β are obtained by immediate filtration of suspension when temperature of reaction mixture is brought to 0° C. and poorly crystalline form γ is obtained when the reaction mixture is stirred for 5-6 hours at 0° C. and then filtered the suspension. In addition to above these forms are also characterized by specific water content. For α form water content should be lower than 4.5%, for β form it should be higher than 4.5% and to obtain γ form, water content should be below 2%.
U.S. Pat. No. 7,709,634 describes an amorphous form of Rifaximin which is prepared by dissolving Rifaximin in solvents such as alkyl esters, alkanols and ketones and precipitating by addition of anti-solvents selected from hydrocarbons, ethers or mixtures thereof.
U.S. Pat. No. 8,193,196 describes two polymorphic forms of Rifaximin, designated δ and ε respectively. Form δ has water content within the range from 2.5 to 6% by weight (preferably from 3 to 4.5%).
U.S. Pat. No. 8,067,429 describes α-dry, β-1, β-2, ε-dry and amorphous forms of Rifaximin.
U.S. Pat. No. 8,227,482 describes polymorphs Form μ, Form π, Form Omicron, Form Zeta, Form Eta, Form Iota and Form Xi of Rifaximin.
International application publications WO 2008/035109, WO 2008/155728, WO 2012/035544, WO 2012/060675, and WO 2012/156533 describes various amorphous or poorly crystalline forms of Rifaximin.
These polymorphic forms are obtained under different experimental conditions and are characterized by XRPD pattern.
The polymorphic forms of Rifaximin obtained from the prior art methods have specific water content. Transition between different polymorphic forms of Rifaximin occurs by drying or wetting of the synthesized Rifaximin. Hence, it is evident from above that Rifaximin can exist in number of polymorphic forms, formation of these polymorphic forms depends upon specific reaction conditions applied during crystallization and drying.
Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, X-ray diffraction pattern, infrared absorption fingerprint, and solid state NMR spectrum. One polymorph may give rise to thermal behaviour different from that of another polymorph. Thermal behaviour can be measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (“TGA”), and differential scanning calorimetry (“DSC”), which have been used to distinguish polymorphic forms.
The differences in the physical properties of different polymorphs results from the orientation and intermolecular interactions of adjacent molecules or complexes in the bulk solid. Accordingly, polymorphs are distinct solids sharing the same molecular formula yet having distinct advantageous physical properties compared to other polymorphs of the same composition or complex.
Considering the importance of Rifaximin, there exists a need to develop an alternate and improved process for the preparation of Rifaximin with better yield. Further, the process involved should be simple, convenient and cost-effective for large scale production. With a view to find a simple process the present applicant diligently worked and identified a robust and economical process for the preparation of Rifaximin. Further, there also remains a need for polymorphic forms which have properties suitable for pharmaceutical processing on a commercial scale. The inventors of the present invention during their continuous efforts developed a novel polymorphic form of Rifaximin.